tbuckley/cabot-search huggingface dataset:
Heterogeneity of tumor immune microenvironment of EGFR/ALK-positive tumors versus EGFR/ALK-negative tumors in resected brain metastases from lung adenocarcinoma
Authors: Gang Xiao, Lifeng Li, Guilong Tanzhu, Zhiyuan Liu, Xuan Gao, Xin Wan, Desheng Xiao, Liu Chen, Xuefeng Xia, Rongrong Zhou
Journal: Journal for ImmunoTherapy of Cancer (2023)

Previous studies found that lung adenocarcinomas (LUAD) with EGFR-positive and ALK-positive were less responsive to immunotherapy, which may be associated with a suppressive tumor immune microenvironment (TIME). Given the discordance in the TIME between primary lung cancer and brain metastasis, it is urgent to explore the TIME in patients with EGFR/ALK-positive LUAD with brain metastases (BMs).The transcriptome feature of formalin-fixed and paraffin-embedded samples of BMs and paired primary LUAD from 70 patients with LUAD BMs was illustrated by RNA-sequencing. Six of them were available for paired sample analysis. Then, after excluding 3 co-occurring patients, we divided 67 BMs patients into 41 EGFR/ALK-positive and 26 EGFR/ALK-negative patients. The differences in immune profiling between the two groups were analyzed from three dimensions: TIME, T-cell receptor repertoire, and immunohistochemistry. Finally, the survival data of 55 patients were collected.Compared with primary LUAD, BMs present an immunosuppressed TIME, manifested as: inhibition of immune-related pathways; low expression of immune checkpoint; decreased infiltration of CD8+T cells and cytotoxic lymphocyte; increased proportion of suppressive M2 macrophages. In different subgroups based on EGFR/ALK gene variation status, both EGFR-positive and ALK-positive tumors present a relatively immunosuppressive microenvironment, but the heterogeneity of tumor microenvironment may undergo different mechanisms. EGFR-positive BMs showed decreased CD8+T cells and increased regulatory T cells (Treg) cells, while ALK-positive BMs showed decreased CD8+T cells and increased M2 macrophages. Moreover, in the TCGA-LUAD cohort, EGFR-positive tumors showed reduced CD8+T cell infiltrations (p<0.001) and borderline significantly higher Tregs than EGFR/ALK-negative (p=0.072). In parallel, ALK-positive tumors had higher median M2 macrophages infiltrations than EGFR/ALK-negative (p=0.175), although there was no statistical significance. Collectively, there was a similar immunosuppressive milieu between EGFR/ALK-positive primary LUAD and BMs. Moreover, survival analysis uncovered higher CD8A expression, cytotoxic lymphocyte infiltration, and immune scores were significantly associated with better prognosis in both EGFR/ALK-positive and EGFR/ALK-negative groups.This study found that LUAD-derived BMs exhibited an immunosuppressive TIME and revealed that EGFR-positive and ALK-positive BMs exhibited different immunosuppressive characteristics. Meanwhile, EGFR-negative BMs showed a potential benefit to immunotherapy. These findings boost molecular and clinical understanding of LUAD BMs.
Global Dynamics of Porcine Enteric Coronavirus PEDV Epidemiology, Evolution, and Transmission
Authors: Hao Zhang, Chuangchao Zou, Ouyang Peng, Usama Ashraf, Qiuping Xu, Lang Gong, Baochao Fan, Yun Zhang, Zhichao Xu, Chunyi Xue, Xiaona Wei, Qingfeng Zhou, Xiaoyan Tian, Hanqin Shen, Bin Li, Xiangbin Zhang, Yongchang Cao
Journal: Molecular Biology and Evolution (2023)

Abstract With a possible origin from bats, the alphacoronavirus Porcine epidemic diarrhea virus (PEDV) causes significant hazards and widespread epidemics in the swine population. However, the ecology, evolution, and spread of PEDV are still unclear. Here, from 149,869 fecal and intestinal tissue samples of pigs collected in an 11-year survey, we identified PEDV as the most dominant virus in diarrheal animals. Global whole genomic and evolutionary analyses of 672 PEDV strains revealed the fast-evolving PEDV genotype 2 (G2) strains as the main epidemic viruses worldwide, which seems to correlate with the use of G2-targeting vaccines. The evolving pattern of the G2 viruses presents geographic bias as they evolve tachytely in South Korea but undergo the highest recombination in China. Therefore, we clustered six PEDV haplotypes in China, whereas South Korea held five haplotypes, including a unique haplotype G. In addition, an assessment of the spatiotemporal spread route of PEDV indicates Germany and Japan as the primary hubs for PEDV dissemination in Europe and Asia, respectively. Overall, our findings provide novel insights into the epidemiology, evolution, and transmission of PEDV, and thus may lay a foundation for the prevention and control of PEDV and other coronaviruses.
Targeted drug delivery to the brain endothelium dominates over passive delivery via vascular leak in experimental intracerebral hemorrhage
Authors: Sahily Reyes-Esteves, Jia Nong, Patrick M. Glassman, Serena Omo-Lamai, Sarah Ohashi, Jacob W. Myerson, Marco E. Zamora, Xiaonan Ma, Scott E. Kasner, Lauren Sansing, Vladimir R. Muzykantov, Oscar A. Marcos-Contreras, Jacob S. Brenner
Journal: Journal of Controlled Release (2023)
Cancer risks with JAKi and biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis or psoriatic arthritis: a national real-world cohort study
Authors: Viking Huss, Hannah Bower, Karin Hellgren, Thomas Frisell, Johan Askling
Journal: Annals of the Rheumatic Diseases (2023)

Assess cancer risks with Janus kinase inhibitors (JAKi) versus biological disease-modifying antirheumatic drugs (bDMARDs) in clinical practice.Cohort study of patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) initiating treatment with JAKi, tumour necrosis factor inhibitors (TNFi) or other (non-TNFi) bDMARDs 2016-2020 using prospectively collected data from the Swedish Rheumatology Quality Register linked to other registers including the Cancer Register. We estimated incidence rates, and HRs via Cox regression, for all cancers excluding non-melanoma skin cancer (NMSC), and for individual cancer types including NMSC.We identified 10 447 patients with RA and 4443 patients with PsA who initiated treatment with JAKi, a non-TNFi bDMARD or a TNFi. Median follow-up times in RA were 1.95, 2.83 and 2.49 years, respectively. In RA, based on 38 incident cancers other than NMSC with JAKi vs 213 with TNFi the overall HR was 0.94 (95% CI 0.65 to 1.38). Based on 59 vs 189 incident NMSC, the HR was 1.39 (95% CI 1.01 to 1.91). At 2 or more years since treatment start, the HR for NMSC was 2.12 (95% CI 1.15 to 3.89). In PsA, based on 5 vs 73 incident cancers other than NMSC, and 8 vs 73 incident NMSC, the corresponding HRs were 1.9 (95% CI 0.7 to 5.2) and 2.1 (95% CI 0.8 to 5.3).In clinical practice, the short-term risk of cancer other than NMSC in individuals initiating treatment with JAKi is not higher than for TNFi, but we found evidence of increased risk for NMSC.
While paradigms shift in von Hippel-Lindau management, questions remain in optimal multidisciplinary neuro-oncology care
Authors: Roy E Strowd
Journal: Neuro-Oncology (2023)

Journal Article While paradigms shift in von Hippel-Lindau management, questions remain in optimal multidisciplinary neuro-oncology care Get access Roy E Strowd Roy E Strowd Departments of Neurology, Internal Medicine, and the Translational Sciences Institute, Comprehensive Cancer Center, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston Salem, NC 27157 Corresponding Author: Roy E. Strowd, III, MD, MEd, MS, FAAN, Neuro-oncologist, Departments of Neurology, Internal Medicine, and the Translational Sciences Institute, Comprehensive Cancer Center, Wake Forest School of Medicine, 1 Medical Center Boulevard, Winston Salem, NC 27157 (rstrowd@wakehealth.edu). Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 5, May 2023, Pages 839–840, https://doi.org/10.1093/neuonc/noad049 Published: 04 March 2023 Article history Published: 04 March 2023 Corrected and typeset: 16 March 2023
The genetic architecture of behavioral canalization
Authors: Robert R.H. Anholt, Trudy F.C. Mackay
Journal: Trends in Genetics (2023)

<h2>Abstract</h2> Behaviors are components of fitness and contribute to adaptive evolution. Behaviors represent the interactions of an organism with its environment, yet innate behaviors display robustness in the face of environmental change, which we refer to as ‘behavioral canalization'. We hypothesize that positive selection of hub genes of genetic networks stabilizes the genetic architecture for innate behaviors by reducing variation in the expression of interconnected network genes. Robustness of these stabilized networks would be protected from deleterious mutations by purifying selection or suppressing epistasis. We propose that, together with newly emerging favorable mutations, epistatically suppressed mutations can generate a reservoir of cryptic genetic variation that could give rise to decanalization when genetic backgrounds or environmental conditions change to allow behavioral adaptation.
Inhibition of ferroptosis through regulating neuronal calcium homeostasis: An emerging therapeutic target for Alzheimer’s disease
Authors: Yiran Sun (孙意冉), Chenchen Yan, Libo He, Shixie Xiang, Pan Wang, Zhonghua Li, Yuanzhao Chen, Jie Zhao, Ye Yuan, Wang Wang, Xiaowei Zhang, Pan Su, Yunfang Su, Jinlian Ma, Jiangyan Xu, Quekun Peng, Huifen Ma, Zhishen Xie, Zhenqiang Zhang
Journal: Ageing Research Reviews (2023)
Exosomes-loaded electroconductive nerve dressing for nerve regeneration and pain relief against diabetic peripheral nerve injury
Authors: Qinfeng Yang, Shenghui Su, Shencai Liu, Sheng Yang, Jing Xu, Yixiu Zhong, Yusheng Yang, Liangjie Tian, Zilin Tan, Jian Wang, Zhiqiang Yu, Zhanjun Shi, Fangguo Liang
Journal: Bioactive Materials (2023)

Over the years, electroconductive hydrogels (ECHs) have been extensively applied for stimulating nerve regeneration and restoring locomotor function after peripheral nerve injury (PNI) with diabetes, given their favorable mechanical and electrical properties identical to endogenous nerve tissue. Nevertheless, PNI causes the loss of locomotor function and inflammatory pain, especially in diabetic patients. It has been established that bone marrow stem cells-derived exosomes (BMSCs-Exos) have analgesic, anti-inflammatory and tissue regeneration properties. Herein, we designed an ECH loaded with BMSCs-Exos (ECH-Exos) electroconductive nerve dressing to treat diabetic PNI to achieve functional recovery and pain relief. Given its potent adhesive and self-healing properties, this laminar dressing is convenient for the treatment of damaged nerve fibers by automatically wrapping around them to form a size-matched tube-like structure, avoiding the cumbersome implantation process. Our in vitro studies showed that ECH-Exos could facilitate the attachment and migration of Schwann cells. Meanwhile, Exos in this system could modulate M2 macrophage polarization via the NF-κB pathway, thereby attenuating inflammatory pain in diabetic PNI. Additionally, ECH-Exos enhanced myelinated axonal regeneration via the MEK/ERK pathway in vitro and in vivo, consequently ameliorating muscle denervation atrophy and further promoting functional restoration. Our findings suggest that the ECH-Exos system has huge prospects for nerve regeneration, functional restoration and pain relief in patients with diabetic PNI.
Designing of gradient scaffolds and their applications in tissue regeneration
Authors: Ananya Pattnaik, A. Swaroop Sanket, Sanghamitra Pradhan, Rajashree Sahoo, Sudiptee Das, Swarnaprbha Pany, Timothy E.L. Douglas, Rambabu Dandela, Qiang Liu, Jaykumar Rajadas, Sanghamitra Pati, Stefaan C. De Smedt, Kevin Braeckmans, Sangram Keshari Samal
Journal: Biomaterials (2023)
Benefits of Bempedoic Acid — Clearer Now
Authors: John H. Alexander
Journal: New England Journal of Medicine (2023)

Vascular atherosclerosis begins in young adulthood and progresses over decades. The condition is associated with considerable morbidity and mortality from coronary, cerebrovascular, and peripheral vascular disease. The foundation of contemporary prevention and treatment of atherosclerosis is lowering the serum cholesterol level with 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins). Statins reduce the low-density lipoprotein (LDL) cholesterol level, slow the progression of atherosclerosis, and reduce the morbidity and mortality associated with coronary, cerebrovascular, and peripheral vascular events.1 High-intensity statin therapy is recommended for all patients with established atherosclerotic vascular disease, as well as those at high risk for atherosclerotic vascular disease.2 Unfortunately, . . .
Epigenetic modifications of inflammation in intervertebral disc degeneration
Authors: Liang Kang, Huaqing Zhang, Chongyu Jia, Renjie Zhang, Cailiang Shen
Journal: Ageing Research Reviews (2023)

Intervertebral disc degeneration (IDD) is a common cause of joint-related chronic disability in elderly individuals worldwide. It seriously impacts the quality of life and inflicts a substantial social and economic burden. The pathological mechanisms underlying IDD have not been fully revealed, leading to less satisfactory clinical treatment outcomes. More studies are urgently needed to reveal its precise pathological mechanisms. Numerous studies have revealed that inflammation is closely related to various pathological processes of IDD, including the continuous loss of extracellular matrix, cell apoptosis, and senescence, indicating the important role of inflammation in the pathological mechanism of IDD. Epigenetic modifications affect the functions and characteristics of genes mainly through DNA methylation, histone modification, non-coding RNA regulation, and other mechanisms, thus having a major effect on the survival state of the body. Recently, the role of epigenetic modifications in inflammation during IDD has been attracting research interest. In this review, we summarize the roles of different types of epigenetic modifications in inflammation during IDD in recent years, to improve our understanding of the etiology of IDD and to transform basic research strategy into a clinically effective treatment for joint-related chronic disability in elderly individuals.
Deubiquitination complex platform: A plausible mechanism for regulating the substrate specificity of deubiquitinating enzymes
Authors: Yi-Zheng Fang, Li Jiang, Qiaojun He, Ji Cao, Bo Yang
Journal: Acta Pharmaceutica Sinica B (2023)

Deubiquitinating enzymes (DUBs) or deubiquitinases facilitate the escape of multiple proteins from ubiquitin‒proteasome degradation and are critical for regulating protein expression levels in vivo. Therefore, dissecting the underlying mechanism of DUB recognition is needed to advance the development of drugs related to DUB signaling pathways. To data, extensive studies on the ubiquitin chain specificity of DUBs have been reported, but substrate protein recognition is still not clearly understood. As a breakthrough, the scaffolding role may be significant to substrate protein selectivity. From this perspective, we systematically characterized the scaffolding proteins and complexes contributing to DUB substrate selectivity. Furthermore, we proposed a deubiquitination complex platform (DCP) as a potentially generic mechanism for DUB substrate recognition based on known examples, which might fill the gaps in the understanding of DUB substrate specificity.
HEALTHCARE DISPARITIES IN PATIENTS WITH CRITICAL LIMB THREATENING ISCHEMIA: INSIGHTS FROM THE NATIONAL INPATIENT SAMPLE DATABASE 2016-2019
Authors: Christian Torres, Francisco Ujueta, Everett Rogers, Matthew R. Lozier, Hernando Torres-Ortiz, Amre Ghazzal, Nirat Beohar
Journal: Journal of the American College of Cardiology (2023)
Papulopustular Rash in Behçet’s Disease
Authors: Andrea Finazzi, Roberto Cosentini
Journal: New England Journal of Medicine (2023)

A 44-year-old woman with recurrent oral aphthous ulcers presented with a progressively worsening papulopustular rash on her face and legs. Skin biopsy of a leg lesion revealed focal small-vessel vasculitis.
Transcatheter Repair for Patients with Tricuspid Regurgitation
Authors: Paul Sorajja, Brian Whisenant, Nadira Hamid, Hursh Naik, Raj Makkar, Peter Tadros, Matthew J. Price, Gagan Singh, Neil Fam, Saibal Kar, Jonathan G. Schwartz, Shamir Mehta, Richard Bae, Nishant Sekaran, Travis Warner, Moody Makar, George Zorn, Erin M. Spinner, Phillip M. Trusty, Raymond Benza, Ulrich Jorde, Patrick McCarthy, Vinod Thourani, Gilbert H.L. Tang, Rebecca T. Hahn, David H. Adams
Journal: New England Journal of Medicine (2023)

Severe tricuspid regurgitation is a debilitating condition that is associated with substantial morbidity and often with poor quality of life. Decreasing tricuspid regurgitation may reduce symptoms and improve clinical outcomes in patients with this disease.We conducted a prospective randomized trial of percutaneous tricuspid transcatheter edge-to-edge repair (TEER) for severe tricuspid regurgitation. Patients with symptomatic severe tricuspid regurgitation were enrolled at 65 centers in the United States, Canada, and Europe and were randomly assigned in a 1:1 ratio to receive either TEER or medical therapy (control). The primary end point was a hierarchical composite that included death from any cause or tricuspid-valve surgery; hospitalization for heart failure; and an improvement in quality of life as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ), with an improvement defined as an increase of at least 15 points in the KCCQ score (range, 0 to 100, with higher scores indicating better quality of life) at the 1-year follow-up. The severity of tricuspid regurgitation and safety were also assessed.A total of 350 patients were enrolled; 175 were assigned to each group. The mean age of the patients was 78 years, and 54.9% were women. The results for the primary end point favored the TEER group (win ratio, 1.48; 95% confidence interval, 1.06 to 2.13; P = 0.02). The incidence of death or tricuspid-valve surgery and the rate of hospitalization for heart failure did not appear to differ between the groups. The KCCQ quality-of-life score changed by a mean (±SD) of 12.3±1.8 points in the TEER group, as compared with 0.6±1.8 points in the control group (P<0.001). At 30 days, 87.0% of the patients in the TEER group and 4.8% of those in the control group had tricuspid regurgitation of no greater than moderate severity (P<0.001). TEER was found to be safe; 98.3% of the patients who underwent the procedure were free from major adverse events at 30 days.Tricuspid TEER was safe for patients with severe tricuspid regurgitation, reduced the severity of tricuspid regurgitation, and was associated with an improvement in quality of life. (Funded by Abbott; TRILUMINATE Pivotal ClinicalTrials.gov number, NCT03904147.).
Synergistic antiviral activity against drug-resistant HIV-1 by naturally occurring dipeptide and A single-stranded oligonucleotide
Authors: Rafael Ceña-Diez, Anna-Lena Spetz, Anders Sönnerborg
Journal: Drug Resistance Updates (2023)

The novel dipeptide WG-am and single-stranded oligonucleotide combination (WG-am:ssON) showed synergistic antiviral activity against HIV-1 integrase-, protease- or reverse transcriptase drug resistant isolates, with over 95% reduction. The highest selectivity indexes were for integrase resistant isolates. WG-am:ssON can be a future option for treatment of HIV drug-resistant strains.
Survivorship: Sexual Dysfunction (Female), Version 1.2013
Authors: Crystal S. Denlinger, Robert W. Carlson, Madhuri Are, K. Scott Baker, Elizabeth Davis, Stephen B. Edge, Debra L. Friedman, Mindy Goldman, Lee Jones, Allison King, Elizabeth Kvale, Terry S. Langbaum, Jennifer A. Ligibel, Mary S. McCabe, Kevin T. McVary, Michelle Melisko, Jose G. Montoya, Kathi Mooney, Mary Ann Morgan, Tracey O’Connor, Electra D. Paskett, Muhammad Raza, Karen L. Syrjala, Susan G. Urba, Mark T. Wakabayashi, Phyllis Zee, Nicole McMillian, Deborah Freedman-Cass
Journal: Journal of the National Comprehensive Cancer Network (2014)

Cancer treatment, especially hormonal therapy and therapy directed toward the pelvis, can contribute to sexual problems, as can depression and anxiety, which are common in cancer survivors. Thus, sexual dysfunction is common in survivors and can cause increased distress and have a significant negative impact on quality of life. This section of the NCCN Guidelines for Survivorship provides screening, evaluation, and treatment recommendations for female sexual problems, including those related to sexual desire, arousal, orgasm, and pain.
The Prognosis of Immaturity
Authors: C. Asher
Journal: BMJ (1946)

<h3>Objective</h3> Disparities in treatment outcomes for traumatic injury are an important concern for care providers and policy makers. Factors that may influence these disparities include differences in risk exposure based on neighbourhood of residence and differences in quality of care between hospitals in different areas. This study examines geographical disparities within a single region: the Detroit metropolitan area. <h3>Design</h3> Data on all trauma admissions between 2006 and 2014 were obtained from the Michigan State Inpatient Database. Admissions were grouped by patient neighbourhood of residence and admitting hospital. Generalised linear mixed modelling procedures were used to determine the extent of shared variance based on these two levels of categorisation on three outcomes. Patients with trauma due to common mechanisms (falls, firearms and motor vehicle traffic) were examined as additional subgroups. <h3>Setting</h3> 66 hospitals admitting patients for traumatic injury in the Detroit metropolitan area during the period from 2006 to 2014. <h3>Participants</h3> 404 675 adult patients admitted for treatment of traumatic injury. <h3>Outcome measures</h3> In-hospital mortality, length of stay and hospital charges. <h3>Results</h3> Intraclass correlation coefficients indicated that there was substantial shared variance in outcomes based on hospital, but not based on neighbourhood of residence. Among all injury types, hospital-level differences accounted for 12.5% of variance in mortality risk, 28.5% of variance in length of stay and 32.2% of variance in hospital charges. Adjusting the results for patient age, injury severity, mechanism and comorbidities did not result in significant reduction in the estimated variance at the hospital level. <h3>Conclusions</h3> Based on these data, geographical disparities in trauma treatment outcomes were more strongly attributable to differences in access to quality hospital care than to risk factors in the neighbourhood environment. Transfer of high-risk cases to hospitals with greater institutional experience in the relevant area may help address mortality disparities in particular.
Gastrointestinal Cancer
Authors: Charles G. Moertel
Journal: JAMA (1976)

GASTROINTESTINAL cancer will afflict 168,000 Americans this year, and 102,000 will die.<sup>1</sup>This incidence exceeds that for any other organ system by a wide margin. Management of cases resistant to traditional curative efforts is, therefore, one of the most commonplace major disease problems encountered in American medical practice. Over the past 17 years, the only accepted tool for specific treatment of advanced gastrointestinal cancer has been fluorouracil (5-FU). This drug has been able to produce only incomplete and transient tumor shrinkage for a small minority of patients (usually in the 15% to 20% range). There is no evidence that such treatment contributes to patient survival regardless of the stage of the disease at which it is applied. Regrettably, intensive research has uncovered no other single drug that exceeds or even matches the limited accomplishments of fluorouracil for the patient with gastrointestinal cancer. Recently, therefore, increased attention has been given